Pharmaceutical compounds

ABSTRACT

A thienopyrimidine of formula (I):  
                 
and the pharmaceutically acceptable salts thereof have activity as inhibitors of PI3K with selectivity for the P110α subtype, and may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour, particularly those associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Processes for synthesizing the compounds are also described.

PRIORITY OF INVENTION

This application claims priority to U.S. Provisional Application No.60/794,966 that was filed on 26 Apr. 2006. The entire content of thisprovisional application is hereby incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to pyrimidine derivatives and their use asinhibitors of phosphatidylinositol 3-kinase (PI3K).

BACKGROUND TO THE INVENTION

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of anumber of phospholipids found in cell membranes. In recent years it hasbecome clear that PI plays an important role in intracellular signaltransduction. In the late 1980s, a PI3 kinase (PI3K) was found to be anenzyme which phosphorylates the 3-position of the inositol ring ofphosphatidylinositol (D. Whitman et al, 1988, Nature, 332, 664).

PI3K was originally considered to be a single enzyme, but it has nowbeen clarified that a plurality of subtypes are present in PI3K. Eachsubtype has its own mechanism for regulating activity. Three majorclasses of PI3Ks have been identified on the basis of their in vitrosubstrate specificity (B. Vanhaesebroeck, 1997, Trend in Biol. Sci, 22,267). Substrates for class I PI3Ks are PI, PI 4-phosphate (PI4P) and PI4,5-biphosphate (PI (4,5)P2). Class I PI3Ks are further divided into twogroups, class Ia and class Ib, in terms of their activation mechanism.Class Ia PI3Ks include PI3K p110α, p110β and p110δ subtypes, whichtransmit signals from tyrosine kinase-coupled receptors. Class Ib PI3Kincludes a p101γ subtype activated by a G protein-coupled receptor. PIand PI(4)P are known as substrates for class II PI3Ks. Class II PI3Ksinclude PI3K C2α, C2β and C2γ subtypes, which are characterized bycontaining C2 domains at the C terminus. The substrate for class IIIPI3Ks is PI only.

In the PI3K subtypes, the class Ia subtype has been most extensivelyinvestigated to date. The three subtypes of class Ia are heterodimers ofa catalytic 110 kDa subunit and regulatory subunits of 85 kDa or 55 kDa.The regulatory subunits contain SH2 domains and bind to tyrosineresidues phosphorylated by growth factor receptors with a tyrosinekinase activity or oncogene products, thereby inducing the PI3K activityof the p 110 catalytic subunit which phosphorylates its lipid substrate.Thus, the class Ia subtypes are considered to be associated with cellproliferation and carcinogenesis.

WO 01/083456 describes a series of condensed heteroaryl derivativeswhich have activity as inhibitors of PI3K and which suppress cancer cellgrowth.

SUMMARY OF THE INVENTION

It has now been found that a particular thienopyrimidine is a potentinhibitor of PI3K with drug-like physicochemical and pharmacokineticproperties. The compound exhibits selectivity for class Ia PI3Ks overclass Ib, in particular for the P110α subtype.

Accordingly, the present invention provides a compound which is athienopyrimidine of formula (I):

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The thienopyrimidine of formula (I) is2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine

A suitable synthetic strategy for producing the compound of theinvention employs the precursor carboxaldehyde of formula (II):

Starting from this precursor the synthesis comprises performing, ineither order, a palladium-mediated (Suzuki-type) cross-coupling reactionand a reductive amination. Thus, a compound of the invention may beprepared by a process which comprises:

(a) treating a compound of formula (II):

with a boronic acid or ester thereof of formula (IV):

in which each R¹⁵ is H or C₁-C₆ alkyl or the two groups OR¹⁵ form,together with the boron atom to which they are attached, a pinacolatoboronate ester group, in the presence of a Pd catalyst; and treating theresulting compound of formula (III):

with an amine of formula (V)

in the presence of a suitable reducing agent; or

(b) treating a compound of formula (II)

with an amine of formula (V)

in the presence of a suitable reducing agent; and treating the resultingcompound of formula (VI):

with a boronic acid or ester thereof of formula

in which each R¹⁵ is H or C₁-C₆ alkyl or the two groups OR¹⁵ form,together with the boron atom to which they are attached, a pinacolatoboronate ester group, in the presence of a Pd catalyst.

Accordingly, the present invention further provides a process forproducing a compound of the invention as defined above, which processcomprises treating a compound of formula (III):

with an amine of formula (V)

in the presence of a suitable reducing agent.

The process thus defined may further comprise producing the compound offormula (III) by treating a compound of formula (II):

with a boronic acid or ester thereof of formula (IV):

in which each R¹⁵ is H or C₁-C₆ alkyl or the two groups OR¹⁵ form,together with the boron atom to which they are attached, a pinacolatoboronate ester group, in the presence of a Pd catalyst.

Yet further, the present invention provides a process for producing acompound of the invention as defined above, which process comprisestreating a compound of formula (VI):

with a boronic acid or ester thereof of formula (IV):

in which each R¹⁵ is H or C₁-C₆ alkyl or the two groups OR¹⁵ form,together with the boron atom to which they are attached, a pinacolatoboronate ester group, in the presence of a Pd catalyst.

The process thus defined may further comprise producing the compound offormula (VI) by treating a compound of formula (II)

with an amine of formula (V)

in the presence of a suitable reducing agent.

A pharmaceutically acceptable salt of a thienopyrimidine of formula (I)may be prepared using conventional techniques. Typically the processcomprises treating the thienopyrimidine of formula (I) as defined abovewith a suitable acid in a suitable solvent.

In the process of the invention as defined above, both the aminationstep and the Pd-mediated cross-coupling step take place underconventional conditions. The palladium catalyst may be any that istypically used for Suzuki-type cross-couplings, such as PdCl₂(PPh₃)₂.The reducing agent is typically a borohydride, for instance NaBH(OAc)₃,NaBH₄ or NaCNBH₄, in particular NaBH(OAc)₃.

The pinacolato boronate ester may be, for instance, prepared by aprocess as described in either of Reference Examples 5 and 6 whichfollow.

A compound of formula (II) as defined above may be prepared by a processwhich comprises treating a compound of formula (VII):

with a lithiating agent followed by N,N′-dimethylformamide (DMF). Thereaction is typically conducted by adding a solution of the lithiatingagent in a non-polar organic solvent, for instance a hydrocarbon solventsuch as hexane, to a suspension of the compound of formula (IX) in anorganic solvent such as tetrahydrofuran (THF). If THF is used theaddition takes place at a low temperature, of about −78° C. Thelithiating agent is typically an alkyllithium, for instancen-butyllithium.

A compound of formula (VII) as defined above may be produced by aprocess which comprises treating a compound of formula (VIII):

with morpholine in an organic solvent. The solvent is typically analcohol, such as methanol. The reaction is generally conducted at roomtemperature.

The compound of formula (VIII) may be prepared by the process describedin Reference Example 1, or by analogy with such a process.

A thienopyrimidine of formula (I) may be converted into apharmaceutically acceptable salt, and a salt may be converted into thefree compound, by conventional methods. Examples of pharmaceuticallyacceptable salts include salts with inorganic acids such as hydrochloricacid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid andphosphoric acid; and organic acids such as methanesulfonic acid,benzenesulphonic acid, formic acid, acetic acid, trifluoroacetic acid,propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,maleic acid, lactic acid, malic acid, tartaric acid, citric acid,ethanesulfonic acid, aspartic acid and glutamic acid. Typically the saltis a mesylate, a hydrochloride, a phosphate, a benzenesulphonate or asulphate. Most typically the salt is a mesylate or a hydrochloride.

The salts, for instance salts with any of the inorganic or organic acidsmentioned above, may be mono-salts or bis-salts. Thus, for example, themesylate salt may be the mono-mesylate or the bis-mesylate.

The compounds of formula (I) and their salts may exist as hydrates orsolvates.

A compound of the present invention has been found in biological teststo be an inhibitor of PI3 kinase. The compound is selective for class IaPI3 kinases over class Ib and typically exhibits at least a 20-foldselectivity for class Ia over class Ib PI3 kinases. In particular, thecompound is selective for the p110α isoform.

A compound of the present invention may thus be used as an inhibitor ofPI3 kinase, in particular of a class Ia PI3 kinase. Accordingly, acompound of the present invention can be used to treat a disease ordisorder arising from abnormal cell growth, function or behaviour. Suchabnormal cell growth, function or behaviour is typically associated withPI3 kinase. Examples of such diseases and disorders are discussed byDrees et al in Expert Opin. Ther. Patents (2004) 14(5):703-732. Theseinclude cancer, immune disorders, cardiovascular disease, viralinfection, inflammation, metabolism/endocrine disorders and neurologicaldisorders. Examples of metabolism/endocrine disorders include diabetesand obesity.

Examples of cancers which the present compounds can be used to treatinclude leukaemia, brain tumours, renal cancer, gastric cancer andcancer of the skin, bladder, breast, uterus, lung, colon, prostate,ovary and pancreas. A human or animal patient suffering from an immunedisorder, cancer, cardiovascular disease, viral infection, inflammation,a metabolism/endocrine disorder or a neurological disorders may thus betreated by a method comprising the administration thereto of a compoundof the present invention as defined above. The condition of the patientmay thereby be improved or ameliorated.

Diseases and conditions treatable according to the methods of thisinvention include, but are not limited to, cancer, stroke, diabetes,hepatomegaly, cardiovascular disease, Alzheimer's disease, cysticfibrosis, viral disease, autoimmune diseases, atherosclerosis,restenosis, psoriasis, allergic disorders, inflammation, neurologicaldisorders, a hormone-related disease, conditions associated with organtransplantation, immunodeficiency disorders, destructive bone disorders,proliferative disorders, infectious diseases, conditions associated withcell death, thrombin-induced platelet aggregation, chronic myelogenousleukemia (CML), liver disease, pathologic immune conditions involving Tcell activation, and CNS disorders in a patient. In one embodiment, ahuman patient is treated with a compound of Formula I and apharmaceutically acceptable carrier, adjuvant, or vehicle, wherein saidcompound of Formula I is present in an amount to detectably inhibit PI3kinase activity.

Cancers which can be treated according to the methods of this inventioninclude, but are not limited to, breast, ovary, cervix, prostate,testis, genitourinary tract, esophagus, larynx, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoidcarcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC),small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma,pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,Hodgkin's and leukemia.

Cardiovascular diseases which can be treated according to the methods ofthis invention include, but are not limited to, restenosis,cardiomegaly, atherosclerosis, myocardial infarction, and congestiveheart failure.

Neurodegenerative disease which can be treated according to the methodsof this invention include, but are not limited to, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, Huntington'sdisease, and cerebral ischemia, and neurodegenerative disease caused bytraumatic injury, glutamate neurotoxicity and hypoxia.

Inflammatory diseases which can be treated according to the methods ofthis invention include, but are not limited to, rheumatoid arthritis,psoriasis, contact dermatitis, and delayed hypersensitivity reactions.

In addition to possessing biochemical potency a compound of theinvention exhibits physicochemical and pharmacokinetic properties whichmakes it particularly well adapted for drug use. This is shown forinstance in the results of the biological assays described in Example 3which follows. In particular the compound possesses high aqueoussolubility at physiological pH; the solubility is greater than 100 μM.High solubility at physiological pH is desirable since it promotesbioavailability.

The compound also possesses high metabolic stability, as shown inparticular by the hepatocyte clearance assay described in Example 3 inwhich the compound was shown to have low hepatocyte clearance. Lowhepatocyte clearance correlates with a low rate of liver metabolism. Itcan therefore be seen that the compound of the present invention possessimproved physicochemical and pharmacokinetic properties whilst retainingbiochemical potency as an inhibitor of PI3 kinase.

A compound of the present invention can be administered in a variety ofdosage forms, for example orally such as in the form of tablets,capsules, sugar- or film-coated tablets, liquid solutions or suspensionsor parenterally, for example intramuscularly, intravenously orsubcutaneously. The compound may therefore be given by injection orinfusion.

The dosage depends on a variety of factors including the age, weight andcondition of the patient and the route of administration. Daily dosagescan vary within wide limits and will be adjusted to the individualrequirements in each particular case. Typically, however, the dosageadopted for each route of administration when a compound is administeredalone to adult humans is 0.0001 to 50 mg/kg, most commonly in the rangeof 0.001 to 10 mg/kg, body weight, for instance 0.01 to 1 mg/kg. Such adosage may be given, for example, from 1 to 5 times daily. Forintravenous injection a suitable daily dose is from 0.0001 to 1 mg/kgbody weight, preferably from 0.0001 to 0.1 mg/kg body weight. A dailydosage can be administered as a single dosage or according to a divideddose schedule.

Typically a dose to treat human patients may range from about 10 mg toabout 1000 mg of a compound of the invention. A typical dose may beabout 100 mg to about 300 mg of the compound. A dose may be administeredonce a day (QID), twice per day (BID), or more frequently, depending onthe pharmacokinetic and pharmacodynamic properties, includingabsorption, distribution, metabolism, and excretion of the particularcompound. In addition, toxicity factors may influence the dosage andadministration regimen. When administered orally, the pill, capsule, ortablet may be ingested daily or less frequently for a specified periodof time. The regimen may be repeated for a number of cycles of therapy.

A compound is formulated for use as a pharmaceutical or veterinarycomposition also comprising a pharmaceutically or veterinarilyacceptable carrier or diluent. The compositions are typically preparedfollowing conventional methods and are administered in apharmaceutically or veterinarily suitable form. The compound may beadministered in any conventional form, for instance as follows:

A) Orally, for example, as tablets, coated tablets, dragees, troches,lozenges, aqueous or oily suspensions, liquid solutions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known in the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose,dextrose, saccharose, cellulose, corn starch, potato starch, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, maize starch, alginic acid, alginates or sodium starchglycolate; binding agents, for example starch, gelatin or acacia;lubricating agents, for example silica, magnesium or calcium stearate,stearic acid or talc; effervescing mixtures; dyestuffs, sweeteners,wetting agents such as lecithin, polysorbates or lauryl sulphate. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and adsorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. Such preparations may be manufactured in a knownmanner, for example by means of mixing, granulating, tableting, sugarcoating or film coating processes.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is present as such, ormixed with water or an oil medium, for example, peanut oil, liquidparaffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia;dispersing or wetting agents may be naturally-occurring phosphatides,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides for example polyoxyethylene sorbitan monooleate.

The said aqueous suspensions may also contain one or more preservatives,for example, ethyl or n-propyl p-hydroxybenzoate, one or more colouringagents, such as sucrose or saccharin.

Oily suspension may be formulated by suspending the active ingredient ina vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol.

Sweetening agents, such as those set forth above, and flavouring agentsmay be added to provide a palatable oral preparation. These compositionsmay be preserved by this addition of an antioxidant such as ascorbicacid. Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, a suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavouring andcolouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids an hexitol anhydrides,for example sorbitan mono-oleate, and condensation products of the saidpartial esters with ethylene oxide, for example polyoxyethylene sorbitanmonooleate. The emulsion may also contain sweetening and flavouringagents. Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, sorbitol or sucrose. In particular a syrup fordiabetic patients can contain as carriers only products, for examplesorbitol, which do not metabolise to glucose or which only metabolise avery small amount to glucose.

Such formulations may also contain a demulcent, a preservative andflavouring and coloring agents;

B) Parenterally, either subcutaneously, or intravenously, orintramuscularly, or intrasternally, or by infusion techniques, in theform of sterile injectable aqueous or oleaginous suspensions. Thissuspension may be formulated according to the known art using thosesuitable dispersing of wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicpaternally-acceptable diluent or solvent, for example as a solution in1,3-butane diol.

Among the acceptable vehicles and solvents that may be employed arewater, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition fattyacids such as oleic acid find use in the preparation of injectables;

C) By inhalation, in the form of aerosols or solutions for nebulizers;

D) Rectally, in the form of suppositories prepared by mixing the drugwith a suitable non-irritating excipient which is solid at ordinarytemperature but liquid at the rectal temperature and will therefore meltin the rectum to release the drug. Such materials are cocoa butter andpoly-ethylene glycols;

E) Topically, in the form of creams, ointments, jellies, collyriums,solutions or suspensions.

F) Vaginally, in the form of pessaries, tampons, creams, gels, pastes,foams or spray formulations containing in addition to the activeingredient such carriers as are known in the art to be appropriate.

Sustained-release preparations of a compound of the invention may beprepared. Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

A compound of the invention may be employed alone or in combination withother therapeutic agents for the treatment of a disease or disorderdescribed herein, such as a hyperproliferative disorder (e.g., cancer).In certain embodiments, a compound of the invention is combined in apharmaceutical combination formulation, or dosing regimen as combinationtherapy, with a second compound that has anti-hyperproliferativeproperties or that is useful for treating a hyperproliferative disorder(e.g., cancer). The second compound of the pharmaceutical combinationformulation or dosing regimen preferably has complementary activities tothe compound of the invention such that they do not adversely affecteach other. Such compounds are suitably present in combination inamounts that are effective for the purpose intended. In one embodiment,a composition of this invention comprises a compound of the invention,in combination with a chemotherapeutic agent such as described herein.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein preferably there is a time period while both (orall) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other chemotherapeutic agents ortreatments.

The invention will be further described in the Examples which follow:

REFERENCE EXAMPLE 1 2,4-Dichloro-thieno[3,2-d]pyrimidine (VIII)

A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85 mmol)and urea (29.75 g, 5 eq.) was heated at 190° C. for 2 h. The hotreaction mixture was then poured onto sodium hydroxide solution and anyinsoluble material removed by filtration. The mixture was then acidified(HCl, 2N) to yield H-thieno[3,2-d]pyrimidine-2,4-dione (IX) as a whiteprecipitate, which was collected by filtration and air dried (9.49 g,66%).

¹H NMR (400 MHz, d₆-DMSO) 6.90 (1H, d, J=5.2 Hz), 8.10 (1H, d, J=5.2Hz), 11.60-11.10 (2H, br s).

A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione (9.49 g, 56.49 mmol)and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. Thereaction mixture was then cooled and poured onto ice/water with vigorousstirring yielding a precipitate. The mixture was then filtered to yield2,4-dichloro-thieno[3,2-d]pyrimidine (VIII) as a white solid (8.68 g,75%)

¹H NMR (400 MHz, CDCl₃) 7.56 (1H, d, J=5.5 Hz), 8.13 (1H, d, J=5.5 Hz).

REFERENCE EXAMPLE 2 2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine

A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine (VIII), (8.68 g, 42.34mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred atroom temperature for 1 h. The reaction mixture was then filtered, washedwith water and MeOH, to yield the title compound as a white solid (11.04g, 100%).

¹H NMR (400 MHz, d₆-DMSO) 3.74 (4H, t, J=4.9 Hz), 3.90 (4H, t, J=4.9Hz), 7.40 (1H, d, J=5.6 Hz), 8.30 (1H, d, J=5.6 Hz).

REFERENCE EXAMPLE 32-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (II)

To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(VII) (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5Msolution of nBuLi in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h,dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirredfor 1 h at −78° C. and then warmed slowly to room temperature. After afurther 2 h at room-temperature the reaction mixture poured ontoice/water yielding a yellow precipitate. This was collected byfiltration and air-dried to yield the title compound (1.50 g, 77%)

¹H NMR (400 MHz, d₆-DMSO) 3.76 (4H, t, J=4.9), 3.95 (4H, t, J=4.9), 8.28(1H, s), 10.20 (1H, s).

REFERENCE EXAMPLE 42-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]yrimidine(VI)

N—BOC-piperazine and methanesulfonyl chloride were reacted together indichloromethane and triethylamine to yield4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester.Cleavage of the BOC protecting group using HCl (2M) in dichloromethaneyielded 1-methanesulfonyl-piperazine. HCl salt.

A mixture of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (II)(1.00 g), 1-methanesulfonyl-piperazine (750 mg) andtrimethylorthoformate (3.80 mL) was stirred in 1,2-dichloroethane (30mL) for 6 hrs at room temperature. To this was added sodiumtriacetoxyborohydride (900 mg) and the reaction mixture was stirred for24 hours at room temperature. The mixture was then quenched with brine,extracted with dichloromethane, dried (MgSO₄) and the solvent removed invacuo. The residue was triturated with hot ethyl acetate to yield thetitle compound (VI) as a white solid (1.01 g).

REFERENCE EXAMPLE 54-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (IVa) Route1

To a solution of 3-bromo-2-methyl aniline (5.0 g, 26.9 mmol) inchloroform (50 mL) was added potassium acetate (1.05 eq., 28.2 mmol,2.77 g). Acetic anhydride (2.0 eq., 53.7 mmol, 5.07 mL) was added withconcurrent cooling in ice-water. The mixture was then stirred at roomtemperature for 10 minutes after which time a white gelatinous solidformed. 18-Crown-6 (0.2 eq., 5.37 mmol, 1.42 g) was then added followedby iso-amyl nitrite (2.2 eq., 59.1 mmol, 7.94 mL) and the mixture washeated under reflux for 18 h. The reaction mixture was allowed to cool,and was partitioned between chloroform (3×100 mL) and saturated aqueoussodium hydrogen carbonate (100 mL). The combined organic extracts werewashed with brine (100 mL), separated and dried (MgSO₄).

The crude product was evaporated onto silica and purified bychromatography eluting with 20%→40% EtOAc-petrol to give1-(4-bromo-indazol-1-yl)-ethanone (A) (3.14 g, 49%) as an orange solid,and 4-bromo-1H-indazole (B) (2.13 g, 40%) as a pale orange solid.

A ¹H NMR (400 MHz, CDCl₃) 2.80 (3H, s), 7.41 (1H, t, J=7.8 Hz), 7.50(1H, d, J=7.8 Hz), 8.15 (1H, s), 8.40 (1H, d, J=7.8 Hz).

B: ¹H NMR (400 MHz, CDCl₃) 7.25 (1H, t, J=7.3 Hz), 7.33 (1H, d, J=7.3Hz), 7.46 (1H, d, J=7.3 Hz), 8.11 (1H, s), 10.20 (1H, br s),

To a solution of the 1-(4-bromo-indazol-1-yl)-ethanone (3.09 g, 12.9mmol) in MeOH (50 mL) was added 6N aqueous HCl (30 mL) and the mixturewas stirred at room temperature for 7 h. The MeOH was evaporated and themixture partitioned between EtOAc (2×50 mL) and water (50 mL). Thecombined organic layers were washed with brine (50 mL), separated anddried (MgSO₄). The solvent was removed by evaporation under reducedpressure to give 4-bromo-1H-indazole (2.36 g, 93%).

To a solution of the 4-bromo-1H-indazole (500 mg, 2.54 mmol) andbis(pinacolato)diboron (1.5 eq., 3.81 mmol) in DMSO (20 mL) was addedpotassium acetate (3.0 eq., 7.61 mmol, 747 mg; dried in drying pistol)and PdCl₂(dppf)₂ (3 mol %, 0.076 mmol, 62 mg). The mixture was degassedwith argon and heated at 80° C. for 40 h. The reaction mixture wasallowed to cool and partitioned between water (50 mL) and ether (3×50mL). The combined organic layers were washed with brine (50 mL),separated and dried (MgSO₄). The crude material was purified bychromatography eluting with 30%→40% EtOAc-petrol to give an inseparable3:1 mixture of the4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (369 mg,60%) and indazole (60 mg, 20%); the title compound (IVa) was isolated asa yellow gum which solidified upon standing to furnish as an off-whitesolid.

¹H NMR (400 MHz, d₆-DMSO) 1.41 (12H, s), 7.40 (1H, dd, J=8.4 Hz, 6.9Hz), 7.59 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=6.9 Hz), 10.00 (1H, br s),8.45 (1H, s), and indazole: 7.40 (1H, t), 7.18 (1H, t, J=7.9 Hz), 7.50(1H, d, J=9.1 Hz), 7.77 (1H, d, J=7.9 Hz), 8.09 (1H, s). Impurity at1.25.

REFERENCE EXAMPLE 64-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (IVa) Route2

To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in aceticacid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) inwater (5 mL). After 2 h, the deep red solution was poured onto ice/waterand the resulting precipitate collected by filtration to yield4-nitro-1H-indazole (67) (1.98 g, 81%).

A mixture of 4-nitro-1H-indazole (760 mg, 4.68 mmol), palladium oncharcoal (10%, cat.) and ethanol (30 mL) was stirred under a balloon ofhydrogen for 4 h. The reaction mixture was then filtered through celite,and the solvent removed in vacuo to yield 1H-indazol-4-ylamine (68) (631mg, 100%).

An aqueous solution of sodium nitrite (337 mg, 4.89 mmol) in water (2mL) was added dropwise to a suspension of 1H-indazol-4-ylamine (631 mg,4.74 mmol) in 6M hydrochloric acid (7.2 mL) at below 0° C. Afterstirring for 30 minutes, sodium tetrafluorobrate (724 mg) was added tothe reaction mixture. A viscous solution resulted, which was filteredand washed briefly with water to yield 1H-indazole-4-diazoniumtetrafluoroborate salt (69) (218 mg, 20%) as a deep red solid.

Dry MeOH (4 mL) was purged with argon for 5 minutes. To this was added1H-indazole-4-diazonium tetrafluoroborate salt (218 mg, 0.94 mmol),bis-pinacolato diboron (239 mg, 1.0 eq.) and[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (20 mg).The reaction mixture was stirred for 5 h and then filtered throughcelite. The residue was purified using flash chromatography to yield thedesired title compound (IVa), (117 mg).

REFERENCE EXAMPLE 72-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[32-d]pyrimidine-6-carbaldehyde(III)

A mixture of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (II)(100 mg, 0.35 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (70) (95mg, 0.39 mmol) and sodium carbonate (112 mg) were suspended in toluene(2.5 mL), ethanol (1.5 mL) and water (0.7 mL). To this was addedbis(triphenylphosphine)palladium(II) chloride (13.5 mg) and the reactionvessel was flushed with argon. The reaction mixture was microwaved at120° C. for 1 h and then partitioned between DCM and water, the organiclayer was washed with brine, dried over magnesium sulfate, filtered andevaporated in vacuo. The resulting residue was purified using flashchromatography to yield the title compound (III) (97 mg).

EXAMPLE 12-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(I)

A mixture of2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(2.00 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole(2.26 g), toluene (24 mL), ethanol (12 mL), water (6 mL), sodiumcarbonate (1.72 g) and PdCl₂(PPh₃)₂ (325 mg) was heated to 130° C. inthe microwave for 90 minutes.

The reaction mixture was cooled, diluted with chloroform, washed withbrine, dried (MgSO₄) and the solvent removed in vacuo. The residue waspurified using flash chromatography (ethyl acetate then 5% ethylacetate/methanol) and then trituration with ether yielded the desiredthe desired title compound (1.4 g) MS data: (ESI+): MH+ 514

NMR data: (CDCl3): 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m),3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 7.41 (1H, s), 7.51(1H, t, J=7.2), 7.60 (1H, d, J=8.3), 8.28 (1H, d, J=7.5), 9.02 (1H, s),10.10 (1H, br)

EXAMPLE 22-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidinebismesylate

To2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(2.00 g, 3.89 mmol) in dichloromethane (50 ml) and methanol (20 ml) wasadded methanesulfonic acid (2 equiv., 505 ul). The reaction mixture wasstirred for 3 hours at room temperature during which time a whiteprecipitate gradually crashed out. Volatiles were removed in vacuo, theresidue was triturated with diethyl ether, the solvent decanted and thesolid dried under vacuum to give the title compound (2.70 g).

NMR (400 MHz, DMSO). Includes the following signals 2.32 (s, 6H), 3.00(s, 3H), 3.84-3.86 (4H, m). 4.09-4.11 (4H, m), 8.8)(1H, s).

EXAMPLE 3 Biological Testing

A compound of the invention, prepared as described above, was submittedto the following series of biological assays:

(i) PI3K Biochemical Screening

Compound inhibition of PI3K was determined in a radiometric assay usingpurified, recombinant enzyme and ATP at a concentration of 1 uM. Thecompound was serially diluted in 100% DMSO. The kinase reaction wasincubated for 1 h at room temperature, and the reaction was terminatedby the addition of PBS. IC₅₀ values were subsequently determined usingsigmoidal dose-response curve fit (variable slope). The compound had anIC₅₀ against PI3K of less than 0.1 μM.

(ii) Cellular Proliferation Inhibition

Cells were seeded at optimal density in a 96 well plate and incubatedfor 4 days in the presence of test compound. Alamar Blue wassubsequently added to the assay medium, and cells were incubated for 6 hbefore reading at 544 nm excitation, 590 nm emission. EC₅₀ values werecalculated using a sigmoidal dose response curve fit. The compound hadan EC₅₀ of 50 uM or less in the range of cell lines utilized.

(iii) Caco-2 Permeability

Caco-2 cells were seeded onto Millipore Multiscreen plates at 1×10⁵cells/cm², and were cultured for 20 days. Assessment of compoundpermeability was subsequently conducted. The compounds were applied tothe apical surface (A) of cell monolayers and compound permeation intothe basolateral (B) compartment was measured. This was performed in thereverse direction (B-A) to investigate active transport. A permeabilitycoefficient value, P_(app), for each compound, a measure of the rate ofpermeation of the compound across the membrane, was calculated.Compounds were grouped into low (P_(app)</=1.0×10⁶ cm/s) or high(P_(app)>/=1.0×10⁶ cm/s) absorption potential based on comparison withcontrol compounds with established human absorption.

For assessment of a compound's ability to undergo active efflux, theratio of basolateral (B) to apical (A) transport compared with A to Bwas determined. Values of B-A/A-B>/=1.0 indicated the occurrence ofactive cellular efflux. The had P_(app) values>/=1.0×10⁶ cm/s.

(iv) Hepatocyte Clearance

Suspensions of cryopreserved human hepatocytes were used. Incubationswere performed at compound concentration of 1 mM or 3 μM at a celldensity of 0.5×10⁶ viable cells/mL. The final DMSO concentration in theincubation was 0.25%. Control incubations were also performed in theabsence of cells to reveal any non-enzymatic degradation. Duplicatesamples (50 μL) were removed from the incubation mixture at 0, 5, 10,20, 40 and 60 minutes (control sample at 60 minutes only) and added toMeOH—containing internal standard (100 L)—to terminate the reaction.Tolbutamide, 7-hydroxycoumarin, and testosterone were used as controlcompounds. Samples were centrifuged and the supernatants at each timepoint pooled for analysis by LC-MSMS. From a plot of ln peak area ratio(parent compound peak area/internal standard peak area) against time,intrinsic clearance (CL_(int)) was calculated as follows: CL_(int)(μl/min/million cells)=V×k, where k is the elimination rate constant,obtained from the gradient of ln concentration plotted against time; Vis a volume term derived from the incubation volume and is expressed asuL 10⁶ cells⁻¹.

On the basis of low (CL</=4.6 μL/min/10⁶ cells), medium (CL>/=4.6;</=25.2 μl/min/10⁶ cells) and high (>/=25.211/min/10⁶ cells) clearance,the compound of the invention was determined to have low hepatocyteclearance.

(v) Cytochrome P450 Inhibition

The compound of the invention was screened against five CYP450 targets(1A2, 2C9, 2C19, 2D6, 3A4) at 10 concentrations in duplicate, with a topconcentration of 100 uM being used. Standard inhibitors (furafylline,sulfaphenazole, tranylcypromine, quinidine, ketoconazole) were used ascontrols. Plates were read using a BMG LabTechnologies PolarStar influorescence mode. The compound displayed weak activity (IC₅₀>/=5 uM)against all isoforms of CYP450.

(vi) Cytochrome P450 Induction

Freshly isolated human hepatocytes from a single donor were cultured for48 h prior to addition of test compound at three concentrations and wereincubated for 72 h. Probe substrates for CYP3A4 and CYP1A2 were addedfor 30 minutes and 1 h before the end of the incubation. At 72 h, cellsand media were removed and the extent of metabolism of each probesubstrate quantified by LC-MS/MS. The experiment was controlled by usinginducers of the individual P450s incubated at one concentration intriplicate. The compound of the invention showed negligible effects oninduction of cytochrome P450 enzymes.

(vii) Plasma Protein Binding

Solutions of test compound (5 μm, 0.5% final DMSO concentration) wereprepared in buffer and 10% plasma (v/v in buffer). A 96 well HT dialysisplate was assembled so that each well was divided in two by asemi-permeable cellulose membrane. The buffer solution was added to oneside of the membrane and the plasma solution to the other side;incubations were then conducted at 37° C. over 2 h in triplicate. Thecells were subsequently emptied, and the solutions for each batch ofcompounds were combined into two groups (plasma-free andplasma-containing) then analysed by LC-MSMS using two sets ofcalibration standards for plasma-free (6 points) and plasma-containingsolutions (7 points). The fraction unbound value for the compound wascalculated: highly protein bound compounds (>/=90% bound) had anFu</=0.1. The compound of the invention had an Fu value>/=0.1.

(viii) hERG Channel Blockage

The compound of the invention was evaluated for its ability to modulaterubidium efflux from HEK-294 cells stably expressing hERG potassiumchannels using established flux methodology. Cells were prepared inmedium containing RbCl and were plated into 96-well plates and grownovernight to form monolayers. The efflux experiment was initiated byaspirating the media and washing each well with 3×100 μL ofpre-incubation buffer (containing low [K⁺]) at room temperature.Following the final aspiration, 50 μL of working stock (2×) compound wasadded to each well and incubated at room temperature for 10 minutes. 50μL of stimulation buffer (containing high [K+]) was then added to eachwell giving the final test compound concentrations. Cell plates werethen incubated at room temperature for a further 10 minutes. 80 μL ofsupernatant from each well was then transferred to equivalent wells of a96-well plate and analysed via atomic emission spectroscopy. Thecompound was screened as 1 pt duplicate IC₅₀ curves, n=2, from a topconcentration of 100 μM.

EXAMPLE 4 Tablet Composition

Tablets, each weighing 0.15 g and containing 25 mg of a compound of theinvention are manufactured as follows:

Composition for 10,000 Tablets

Active compound (250 g)

Lactose (800 g)

Corn starch (415 g)

Talc powder (30 g)

Magnesium stearate (5 g)

The active compound, lactose and half of the corn starch are mixed. Themixture is then forced through a sieve 0.5 mm mesh size. Corn starch (10g) is suspended in warm water (90 mL). The resulting paste is used togranulate the powder. The granulate is dried and broken up into smallfragments on a sieve of 1.4 mm mesh size. The remaining quantity ofstarch, talc and magnesium is added, carefully mixed and processed intotablets.

EXAMPLE 5 Injectable Formulation

Formulation A Active compound 200 mg Hydrochloric Acid Solution 0.1M or4.0 to 7.0 Sodium Hydroxide Solution 0.1M q.s. to pH Sterile water q.s.to  10 mL

The compound of the invention is dissolved in most of the water (35° 40°C.) and the pH adjusted to between 4.0 and 7.0 with the hydrochloricacid or the sodium hydroxide as appropriate. The batch is then made upto volume with water and filtered through a sterile micropore filterinto a sterile 10 mL amber glass vial (type 1) and sealed with sterileclosures and overseals. Formulation B Active Compound 125 mg Sterile,Pyrogen-free, pH 7 Phosphate Buffer, q.s. to 25 mL Active compound 200mg Benzyl Alcohol 0.10 g Glycofurol 75 1.45 g Water for injection q.s to3.00 mL

The active compound is dissolved in the glycofurol. The benzyl alcoholis then added and dissolved, and water added to 3 mL. The mixture isthen filtered through a sterile micropore filter and sealed in sterile 3mL glass vials (type 1).

EXAMPLE 6 Syrup Formulation

Active compound 250 mg Sorbitol Solution 1.50 g Glycerol 2.00 g Sodiumbenzoate 0.005 g Flavour 0.0125 mL Purified Water q.s. to 5.00 mL

The compound of the invention is dissolved in a mixture of the glyceroland most of the purified water. An aqueous solution of the sodiumbenzoate is then added to the solution, followed by addition of thesorbital solution and finally the flavour. The volume is made up withpurified water and mixed well.

1. A compound which is a thienopyrimidine of formula (I):

or a pharmaceutically acceptable salt thereof.
 2. A compound accordingto claim 1 wherein the pharmaceutically acceptable salt is selected fromsalts with hydrochloric acid, hydrobromic acid, hydroiodic acid,sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid,benzenesulphonic acid, formic acid, acetic acid, trifluoroacetic acid,propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,maleic acid, lactic acid, malic acid, tartaric acid, citric acid,ethanesulfonic acid, aspartic acid and glutamic acid.
 3. A compoundaccording to claim 1 wherein the pharmaceutically acceptable salt is amono-salt or a bis-salt.
 4. A compound according to claim 1 which is amono-salt or a bis-salt with methanesulphonic acid, benzenesulphonicacid, hydrochloric acid, phosphoric acid and sulphuric acid.
 5. Acompound according to claim 1 which is2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidinebismesylate.
 6. A process for producing a compound as defined in claim1, which process comprises treating a compound of formula (III):

with an amine of formula (V)

in the presence of a suitable reducing agent.
 7. A process according toclaim 6 which further comprises producing the compound of formula (III)by treating a compound of formula (II):

with a boronic acid or ester thereof of formula (IV):

in which each R¹⁵ is H or C₁-C₆ alkyl or the two groups OR¹⁵ form,together with the boron atom to which they are attached, a pinacolatoboronate ester group, in the presence of a Pd catalyst.
 8. A process forproducing a compound as defined in claim 1, which process comprisestreating a compound of formula (VI)

with a boronic acid or ester thereof of formula (IV):

in which each R¹⁵ is H or C₁-C₆ alkyl or the two groups OR¹⁵ form,together with the boron atom to which they are attached, a pinacolatoboronate ester group, in the presence of a Pd catalyst.
 9. A processaccording to claim 8, which further comprises producing the compound offormula (VI) by treating a compound of formula (II)

with an amine of formula (V)

in the presence of a suitable reducing agent.
 10. A process forproducing a pharmaceutically acceptable salt as defined in claim 1,which process comprises treating a thienopyrimidine of formula (I):

with a suitable acid in a suitable solvent.
 11. A process according toclaim 10, wherein the acid is selected from hydrochloric acid,hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid,phosphoric acid, methanesulfonic acid, benzenesulphonic acid, formicacid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid,malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,malic acid, tartaric acid, citric acid, ethanesulfonic acid, asparticacid and glutamic acid.
 12. A process according to claim 10, wherein theacid is selected from methanesulphonic acid, benzenesulphonic acid,hydrochloric acid, phosphoric acid and sulphuric acid.
 13. Apharmaceutical composition which comprises a pharmaceutically acceptablecarrier or diluent and, as an active ingredient, a compound as claimedin claim
 1. 14. A composition according to claim 13 which is formulatedfor oral administration. 15-21. (canceled)
 22. A method of treating adisease or disorder arising from abnormal cell growth, function orbehaviour, which method comprises administering to a patient in needthereof a compound as defined in claim
 1. 23. A method according toclaim 22 wherein the abnormal cell growth, function or behaviour isassociated with PI3 kinase.
 24. A method according to claim 22 whereinthe disease or disorder is selected from the group consisting of cancer,immune disorders, cardiovascular disease, viral infection, inflammation,metabolism/endocrine disorders and neurological disorders.
 25. A methodaccording to claim 24, wherein the disease or disorder is selected fromcancer, immune disorders, cardiovascular disease, viral infection,inflammation, metabolism/endocrine disorders and neurological disorders.26. A method according to claim 24, wherein the cancer is selected fromglioblastoma, melanoma, prostate, endometrial, ovarian, breast, lung,head and neck, hepatocellular, and thyroid cancers.
 27. A methodaccording to claim 24, wherein the cancer is selected from breast,ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx,glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung,epidermoid carcinoma, large cell carcinoma, non-small cell lungcarcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone,colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system.Hodgkin's and leukemia.
 28. A process for producing a pharmaceuticalcomposition which process comprises combining a compound as defined inclaim 1 with a pharmaceutically acceptable carrier.
 29. A kit fortreating a PI3K-mediated condition, comprising: (a) a firstpharmaceutical composition comprising a compound as defined in claim 1;and (b) instructions for use.
 30. A kit according to claim 29, furthercomprising (c) a second pharmaceutical composition, wherein the secondpharmaceutical composition comprises a second compound havinganti-hyperproliferative activity.
 31. A kit according to claim 30further comprising instructions for the simultaneous, sequential orseparate administration of said first and second pharmaceuticalcompositions to a patient in need thereof.
 32. A kit according to claim30, wherein said first and second pharmaceutical compositions arecontained in separate containers.
 33. A kit according to claim 30,wherein said first and second pharmaceutical compositions are containedin the same container.
 34. A product comprising (a) a compound asdefined in claim 1; and (b) a compound having anti-hyperproliferativeactivity; for separate, simultaneous or sequential administration in theprophylactic or therapeutic treatment of cancer.